N-acylated perfluoroalkanesulfonamides

ABSTRACT

This invention relates to certain N-acyl aliphatic sulfonamides and salts thereof which are active as herbicides. Many of the compounds of this invention are also physiologically active as diuretics and/or anticonvulsants. Processes for the preparation of the compounds and compositions for horticultural use containing these compounds are described.

United States Patent [1 13,622,626

[72] Inventor George G. 1. Moore 7 [50] Field of Search 260/556 C, White Bear Lake, Minn. 556 F, 556 AC 211 Appl. N0. 784,877

221 Filed Dec. 18, 1968 References Cited 45 Patented Nov. 23, 1971 UNITED STATES PATENTS 1 Assignee Minnesota Mining and Manufacturing 3,041,374 6/ 1 962 Gregory 260/556 c p y 3,439,018 4/l969 Brookes et al. 260/556 c St. Pa Mi m Primary Examiner-Henry R. .Iiles Assistant Examiner-S. D. Winters 54 CYL T Anorney Kinney, Alexander, Sell, Steldt & Delahunt PERFLUOROALKANESULFONAMIDES 4 No Drawmgs ABSTRACT: This invention relates to certain N-acyl aliphatic n 1 sulfonamides and salts thereof which are active as herbicides.

260/556 260/544 260/559 3, 260/553 Many of the compounds of this invention are also physiologi- 260/543 1 424/321, 1 1 cally active as diuretics and/or anticonvulsants. Processes for [5 Int the preparation of the compounds and compositions for her. ticultural use containing these compounds are described.

N-ACYLATED PERFLIJOROALKANESULFONAMIDES BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to N-substituted alkane sulfonamides and to herbicides and other physiologically active substances,

e .g. anticonvulsants and/or diuretics.

2. Prior Art Alkane sulfonamides and haloalkane sulfonamides are known to the art. So far as is known, no N-acylated aliphatic sulfonamides have been reported prior to the present inven- I IIOI'I.

SUMMARY OF THE INVENTION This invention relates to N-(aryloxaacyl) or N- (arylthiaacyl) aliphatic sulfonamides, and more particularly to compounds of formula I:

( ain wherein A is oxygen or sulfur, R, is a divalent lower alkylene linking radical, R is an aliphatic or haloaliphatic radical having from one to eight carbon atoms, R is halogen, nitro, lower alkyl, lower alkoxy, lower haloalkyl, and alkanoyl and alkenoyl radicals having from two to six carbon atoms; n is an integer from zero to five; and salts thereof involving the hydrogen atom of the amido nitrogen atom.

The term aliphatic" as used herein means a straight or branched carbon chain radical containing from one to eight carbon atoms and preferably containing not more than about four carbon atoms. It may be substituted by halogen, and compounds wherein R is perfluoroalkyl are presently preferred.

The terms alkonoyl" and alkenoyl as used herein refer to alkyl or alkenyl carbonyl substituents such as acetyl, propionyl, hexanoyl, acryloyl and the like having two to six carbon atoms.

The amido nitrogen atom of the compounds of formula I bears a hydrogen atom which is relatively acidic. It may be replaced by metal ions by neutralization with a salt of a weak acid. Suitable metal ions which may be utilized are preferably those which are pharmaceutically or horticulturally acceptable, for example sodium and potassium, when the compounds of the invention are to be used as anticonvulsants. Other pharmaceutically acceptable cations, which are well known to the art, may also be included in salts of the compounds of the invention. In order to prepare salts of compounds of formula I for horticultural or agricultural purposes, a variety of commonly used metal salts, for example alkali metal, alkaline earth metal and heavy metal, such as iron and zinc, salts may also be prepared by ordinary neutralization reactions of the compounds of formula I.

v v Exemplary of compounds of this invention are:

N-( 2',4'-dichlorophenoxyacetyl )-2-chloroethanesulfonamide,

N-(4'-chlorophenoxyacetyl )isobutanesulfonamide,

N-( 3 '-trifluoromethylphenoxyacetyl )trifluoromethanesulfonamide,

N-( 3 '-nitrophenoxyacetyl ltrifluoromethanesulfonamide,

2 N-[ 2-( 4'-chlorophenoxy )isobutyrylltrifluoromethanesulfonamide,

N-(4'-chlorothiophenoxyacetyl)trifluoromethanesulfonamide,

N-(4'-chlorophenoxyacetyl)perfluoroethanesulfonamide, N-( pentafluorophenoxyacetyl)trifluoromethanesulfonamide,

N-(4'-chlorophenoxyacetyl)perfluorobutanesulfonamide, N-(4'-chlorophenoxyacetal)trifluromethanesulfonamide, N-(2',4-dichlorophenoxyacetyl)trifluoromethanesulfonamide,

N-(2',4',5-trichlorophenoxyacetyl)trifluoromethanesulfonamide,

N-[ 2-( 2' ,4 ,5 '-trichlorophenoxy )propionyl] trifluoromethanesulfonamide,

N-phenoxyacetyltrifluromethanesulfonamide, yacetyltrifluoromethanesulfonamide,

N-(2'-chlorophenoxyacetyl)trifluoromethanesulfonamide, N-(3'-chlorophenoxyacetyl)trifluoromethanesulfonamide, N-( 4'-fluorophenoxyacetyl)trifluoromethanesulfonarnide, and

N-(2-methyl-4'-chlorophenoxyacetyl)trifluoromethanesulfonamide,

Starting materials of formula II and formula III are known to the art or are readily prepared using known techniques.

The compounds of the invention are prepared conveniently by the reaction of an acyl halide with an aliphatic sulfonamide or its salt as shown in the following equation:

henox- (Rt). m

In this equation A, R R R and n are as defined above, M is hydrogen or a metal ion, and X is halogen, preferably chlorine, since the acyl chlorides are generally more conveniently available.

It is preferred that the reaction be run in the presence of base, although base is not necessary and a nonreactive solvent is preferred. Generally this solvent has been acetone, but other solvents including alkyl ketones, esters, monoand diglyme, benzene, alkanes, chlorinated hydrocarbons and the like can be used. It is preferred that these solvents dissolve most of the reactants to facilitate homogeneous reaction. Bases which are suitable include salts of weak acids such as sodium acetate and sodium carbonate and organic tertiary amines such as triethylamine and N,N-dimethylaniline. The reaction is preferably run under anhydrous conditions, and when very active acyl halides are used. under an atmosphere of a relatively inert gas such as nitrogen.

These reactions may also be run in high pressure reactors,

without solvent.

An alternative route to some of the compounds of this invention is available. This consists of the reaction of an amide, or its salt, with an aliphatic sulfonyl halide, as shown in the following equation:

wherein A, R,, R R n, M and X are as defined above. However, this route is generally not preferred.

For general use as anticonvulsants, the compounds of the present invention are preferably administered orally. For oral administration they will preferably be administered as salts of pharmaceutically acceptable cations, as are well known to the art, and particularly as sodium salts.

The amounts of the compounds of formula I which are to be administered will depend on the age and weight of the warmblooded animal recipient. Generally, the compounds of this invention should be administered in doses of 0.1 to 20 milligrams per kilogram daily. The amounts can be given in single or multiple doses, as required. The particular dosage for any given situation will be apparent to one skilled in the art.

The compounds of formula I or their pharmaceutically acceptable salts can be suitably formulated in physiologically acceptable solutions and carriers to make tablets, syrups, isotonic solutions, injectable solutions, suppositories and other dosage forms.

in order to examine the efficacy of the compounds of the present invention in the prevention or reduction in severity of convulsive seizures, they were tested by two methods, electroshock and chemically induced shock. More specifically, supramaximal electroshock and pentamethylenetetrazole-induced seizures were used as test methods.

The supramaximal electroshock technique is described in detail by Toman et al., Journal of Neurophysiology 9:23] (1946).

For the purpose of screening the compounds of the invention, mice or rats are given supramaximal electroshocks of 50mA (mice) or l50mA (rats) of 60 c.p.s. alternating current for 0.2 second through corneal electrodes. At various intervals after the administration of the compounds the animals are checked for the absence of tonic extension of the hind limbs following shock. Untreated or vehicle pretreated control animals invariably exhibit tonic hind limb extension in this procedure.

In order to obtain a correlation of the effectiveness of the protection with the lethal hazard, the dose (ED that protects 50 percent of the animals at the time of peak antishock effect is calculated, and is compared to the median neurotoxic dose, TD A protective index (P.l.=TD,, /ED is calculated. In order to determine the ED groups of animals receive different doses of the test compounds, and each animal is shocked only once.

The production of pentamethylenetetrazole-induced seizure is described in detail by Everett and Richards, Journal of Pharmacology and Experimental Therapeutics 8], 402 (1944).

For the screening of the compounds of the present invention, the following procedure was followed.

Groups of six to 10 male mice (l8-26 g.), caged individually, are administered the test compound at suitable geometrically spaced dosage levels. At various times thereafterteg. I5, 30, 60, 120 minutes), 1.0 percent pentamethylenetetrazole is injected subcutaneously in a dose of 100 mg./kg. and the time of injection noted for each mouse. Recorded end-points for (l first twitch, (2) sustained, dominantly clonic seizure activity with or without loss of righting, (3) tonic extension of hind limbs, and (4) death are noted for each mouse following pentamethylenetetrazole challenge. Groupmeans and standard errors are calculated for each treatment group and compared with the corresponding values in a pretreated control group. Antagonism of pentamethylenetetrazole-induced seizures is seen in a reduction of the incidence of these events within a treatment group, or by an increase in the latency of these events.

As used herein and in the appended claims the term herbicide means materials having a modifying effect on the growth of plants. Such modifying effects include all deviations from natural development, for example killing, defoliation, stimulation, stunting, retardation, desiccation, tillering, dwarfing, growth regulation and the like.

The herbicidal (weed-killing) activity of representative compounds of the invention was determined using screening tests against experimental plantings. Both preand postemergence activities were determined in a direct screen against selected weed species. The'following weed mixtures were used for the tests.

Grasses Giant foxtail (Setaria faberii) Barnyard grass (Echinochloa crusgalli) Crabgrass (Digitaria ischaemum) Quackgrass (Agropyron repens) Broadleaves Pigweed (Amaranthus retroflexus) Purslane (Portulaca oleracea) Wild mustard (Brassica kaber) Wild morning glory (Convolvulus arvensis) The test chemicals were dissolved in a small amount of acetone or other suitable solvent and then diluted with water to give a concentration of 2,000 p.p.m. From this concentration aliquots were diluted to give a final concentration of 500 p.p.m. Eighty ml. of this solution were added to a 6-inch pot containing the weed seeds to give a concentration equivalent to 20 lb./acre.

To assess post emergence activity, the same weed mixtures were allowed to grow from 2 to 3 weeks until the grasses were approximately I to 3 inches and the broadleaves i k-inches tall. They were sprayed for approximately 10 seconds or until good wetting of the leaf surfaces occurred with a 2,000 p.p.m. solution as described above.

The following compounds of the invention were all active at 20 pounds per acre or 2,000 p.p.m. or less:

N (4'-chlorophenoxyacetyl)trifluoromethanesulfonamide, N (2,4'-dichlorophenoxyacetyl)trifluoromethanesulfonamide, N-(2,4,5'-trichlorophenoxyacetyDtrifluoromethanesulfonamide, and N-[2-(2.4,5')trichlorophenoxy)propionyll trifluoromethanesulfonamide.

In order to control unwanted plants the compounds of the invention can be used alone as herbicides, for example as dusts or granules of the compounds, or preferably they may be applied in formulations. The formulations are comprised of active ingredients and one or more herbicidal adjuvants and/or carriers. Formulations are useful to facilitate the application of the compounds and to achieve specific biological objectives such as controlling the availability of the herbicide, improving adherence to plants, and the like, as is well known to those skilled in the art.

The compounds of the invention may be formulated as wettable powders, emulsifiable concentrates, aqueous or nonaqueous solutions and/or suspensions, granules, dusts and the like. Said compounds can be finely divided and suspended in any of the usual aqueous media. Spreading agents, wetting agents, sticking agents or other adjuvants can be added if desired.

When emulsifiable concentrates are prepared the active ingredient can be in a concentration of about 5 percent to 60 percent or more, depending upon its solubility. The units of concentration are weight per unit weight. The active ingredients are soluble in common organic horticultural solvents such as benzene, toluene, xylene, dichloromethane, chloroform, hexane and heptane or less highly refined aromatic or aliphatic hydrocarbons and mixtures thereof. Examples of these are coal tar fractions, straight run petroleum distillates, therrnolytically or catalytically cracked hydrocarbon oil, gas oil, light lubricating oil fractions, kerosene, mineral seal oil, and the like. In appropriate cases oxygenated solvents such as ketones may be used in or as the carriers. These concentrates can be dispersed in water to permit the use of an aqueous spray. Admixture with a small amount of an organic surface active agent capable of lowering the surface tension of water is preferred.

Examples of surface active agents variously known as dispersing agents, wetting agents or emulsifying agents comrise soft or hard soaps morpholine or dimethylamine oleate, sulfonated fish, castor and petroleum oils, sodium salt of lignin sulfonic acid, alkylated aromatic sodium sulfonates, such as decylbenzene sodium sulfonate, dodecylbenzene sodium sulfonate, butyl or other amine salts of decyl or dodecylbenzene sulfonic acid, sodium lauryl sulfate, disodium monolauryl phosphate, ethylene oxide condensation products of alkyl phenols, as for example octyl phenol, ethylene oxide condensation products of tall oil, ethylene oxide condensation products of high alcohols or higher mercaptans. Mixtures of two or more surface active agents are also feasible. Generally, the surface active agent will comprise only a small proportion of the composition, say 0.1- percent by weight of the toxicant.

The formulation of dry compositions for application as granules, dusts or for further dilution with liquid carriers is readily accomplished by mixing the toxicant with a solid carrier. Such solid carriers will be of various sizes from dusts to granules. The techniques for such formulations are well known to the art. Suitable carriers include charcoal, talc, clay, pyrophyllite, silicas, fullers earth, lime, diatomaceous earth, flours such as walnut shell, wheat, soya bean, cottonseed and wood flours, magnesium and calcium carbonate, calcium phosphate and the like. Powders may be granulated by the use of suitable binders such as cellulose derivatives, for example ethyl or carboxymethyl, corn syrup, and the like. The compounds or the above formulations are applied by spraying, spreading, dusting or the like. The rate of application will of course vary, but the more active compounds of the invention exhibit satisfactory control of broadleaf and grass weeds at the application rate of about 5 to 30 lbs. per acre. It is of course to be expected that local conditions, for example temperature, humidity, moisture content of the soil, nature of the soil, and the like, may require greater or smaller amounts. Effective resolution of these factors is within the skill of those versed in the herbicidal art. Likewise it is apparent that not all of the compounds included within the scope of the invention have equal activity.

The herbicidal compositions may contain one or more of the herbicidal N-acylated aliphatic sulfonamides set out hereinbefore as the sole active species, or they may contain in addition thereto other biologically active substances. Thus insecticides and fungicides may be incorporated in the compositions. Further, if desired, the herbicidal compositions may contain fertilizers, trace metals or the like and when applied directly to the soil may additionally contain nematicides, soil conditioners, plant growth regulators and/or herbicides of similar or different properties.

Certain compounds of this invention have also shown activity as diuretics.

In order to further illustrate the invention following nonlimiting examples are provided. Melting points are uncorrected.

EXAMPLE 1 N-Acylfluoroalkanesulfonamides: General Procedure A mixture of fluoroalkanesulfonamide (0.1 mole), sodium carbonate (0.2 mole) and acetone (about 200 ml.) is stirred l or more hours under a nitrogen atmosphere. The acid chloride (0.1 mole) diluted with a small amount of acetone is added over I or more hours. A mild exotherm is sometimes observed. The reaction mixture is stirred under nitrogen for l or more hours, the mixture is filtered and the acetone is removed in vacuo. The product is a sodium salt, usually solid but sometimes a sticky gum, of the corresponding compound of formula l. Dissolution in water, treatment with decolorizing charcoal and filtration may be used to partially purify the product. The product is reisolated by evaporation as the sodium salt, or acidification of the filtrate may be used to obtain the product compound of formula I. Some of these products have an appreciable water solubility. Recrystallization of compounds of formula I is usually carried out from trichloroethylene, nitromethane or mixtures of aromatic and aliphatic hydrocarbons such as benzenehexane.

EXAMPLE 2 A mixture of trifluoromethane sulfonamide (657 g., 4.4 moles), sodium carbonate (954 g., 9.0 moles) and acetone (3 liters) is stirred 70 hours. Crude N-2,4-dichlorophenoxyacetyl chloride (1 kg., 4.5 moles) is added over 3 hours (exothermic) and the mixture is stirred 48 hours. lt is then filtered through an inorganic filter media (Super-eel), evaporated in vacuo to dryness and washed with diethyl ether to yield a white powder. This powder is blended with water and the paste is stirred into water (total volume 14 liters) and treated with decolorizing charcoal. The mixture is then filtered and the colorless solution is acidified with 150 ml. of concentrated hydrochloric acid. The white solid is collected, washed once with water and dried to yield N-(2',4-dichlorophenoxyacetyl)trifluorometh anesulfonamide, m.p. lO2-l l0 C. Anal. Calculated for C H CIF NO S: C, 30.7; H, 1.7; N, 4.0 Found: C, 31.1;l-l, l.7;N, 3.8.

The following compounds are prepared according to the procedure of example I.

Melting Ex. Point No. Compound (in C.)

3 N-(4'-chluropltenoxyacetyl)methanesulfon-amidc IM- 4 N-(4'-chlorophenoxyacetyl)tril'luoromethun esulfonamide I43- I 44 5 N-(2,4'-dichlorophenoxyucetyl)tril'luoromelh anesulfonumide IUZ-l l0 6 N-(2',4',5'-trichloruphenoxyuc:tyl)trifluoromct hanesulfonumide MTV-108.5

7 N-[2-( 2'.4,5-trichlorophenoxy)propionyl)- trilluoromethanesulfonamidc -93 8 N-phcnoxyucetyltrifluoromethunesull'onumide I 34- l 3 5 9 N-( 2-chlorophenoxyacctyl )tril'luoromethun esulfonamide ll3.5-l l5 IO N-( 3-chlorophenoxyucetyl )trilluoromcthun esulfonamide l5 l l 5 2 l l N-(4-lluorophenoxyacetyl)trifluornmcthun esull'onurnide I 35- l 36 I2 N-(2-methyl-4" chlorophenuxyacelyl)lriflueromethan esullonamide I20- I 2 I I3 N-( 3 '-trifluoromethylphenoxyacetyl )triflu oromethanesulfonarnide l46-l47.5 l4 N (3'-nitrophenoxyacetyl)lrifluoromethune sulfonamide l55-l57 l5 N-l 2-(4-chlorophenoxy )isobutyryl) trifluoromethanesulfonamide 80-82 16 N-(4'-chlorothiuphenoxyucetyl)trifluorome lhanesulfunamide l lO-l l2 l7 N-(4'-chlorophenoxyucetyl)perfluoroethane sulfonumide l33l36 18 N-( pentafluorophenoxyacetyl )trilluo romethancsulfonamide 9o l9 N-(4-chlorophenoxyacetyl)pcrfluorobulun:

sulfonamide I53. l-l56 20 N- I 2.3-dichloro-4-( l-mcthylenebutyryl phenuxylucetyl} lrilluorumelhunesulfonnmide 97-995 What is claimed is:

l. A compound of the formula 2. N-(4-chlorophenoxyacetyl)trifuluoromethanesulfonamide.

3. N-( 2' ,4-dichlorophenoxyacetyl )trifluoromethanesulfonamide.

4. N-( 2' ,4 ,5 '-trichlorophenoxyacetyl )trifluoromethanesulfonamide.

* II t i i UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,622,626 Dated November 23 1971 Inventor(s) orge G. I Moore It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 37, insert at the beginning of the line --The term "lower" when applied-- Column 1, line 50, "alkonoyl" should read --alkanoyl-- Column 2, line 16, at the end of the line, delete "henox-". Column 2, line 17, delete "yacetyltriiluoromethanesulfonamide,". Column 6, line 30, "C H ClF NO S" should read --C H Cl F NO S-- Column 6,

line 6 1, a bracket (E) should be inserted before 2'.

Signed and sealed this 19th day of September 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

2. N-(4''-chlorophenoxyacetyl)trifuluoromethanesulfonamide.
 3. N-(2'',4''-dichlorophenoxyacetyl)trifluoromethanesulfonamide.
 4. N-(2'',4'',5''-trichlorophenoxyacetyl)trifluoromethanesulfonamide. 